Investigating the Mechanisms of Tumor Suppression Mediated by PTEN PDZ-binding Domain in a Murine Breast Cancer Model
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AbstractPTEN (Phosphatase and tensin homolog) functions as a key negative regulator of PI3K-Akt pathway through its lipid phosphatase activity. Mutations or loss of PTEN is frequently observed in brain, breast, prostate and endometrial cancer. PTEN possesses a PDZ-binding domain (PDZ-BD) at the end of its carboxyl terminus. Functionally, PDZ-BD mediates PTEN’s interactions with other PDZ domain-containing proteins, including ZO-1, PSD-95, DLG, etc. Functionally, these PDZ-domain containing proteins are involved in the formation of cell junctions, post-synaptic densities, and more importantly, serving as scaffolding proteins for multiple signaling complexes. Besides, somatic mutations in human cancer have been recorded within the PTEN PDZ-binding domain, or in the carboxyl terminus that will lead to the truncation of this domain. However, whether the PTEN PDZ-binding domain is required to suppress tumorigenesis still remains obscure.

To study the role of PTEN PDZ-BD in breast epithelial tumorigenesis, a PTEN-ΔPDZ mice lacking this domain was generated. PTEN expression level and activity of PI3K-Akt pathway are not changed in the primarily cultured mammary epithelium of PTEN-ΔPDZ mice. Therefore, PDZ-BD is dispensable for PTEN stability and negative regulation of the PI3K-Akt pathway. Further, we crossed the PTEN-ΔPDZ mice with the MMTV-PyMT breast cancer model to induce mammary tumorigenesis. As a result, we observed increased total tumor burden as well as higher tendency of lung metastasis in PTEN-ΔPDZ mice. This data indicates that PTEN PDZ-BD is indeed important for tumor suppression during breast cancer progression. Besides, we showed that the increased tumor burden in PTEN-ΔPDZ mice are not due to either increased proliferation (Ki-67 staining) or decreased apoptosis (cleaved caspase-3 staining).

Previously, PTEN has been reported to govern the integrity of tight junctions and apical-basal polarity of epithelial cells, which requires PTEN’s interactions with other proteins through the PDZ-BD. However, through in vitro three-dimensional culture of primary mouse mammary epithelial cells and examination of tight junctions of MMTV-PyMT breast cancer tissue by transmission electron microscopy (TEM), we failed to observe any disruption of either apical-basal polarity or tight junction. Meanwhile, we investigated the alteration of the transcriptome of breast cancer tissue in PTEN-ΔPDZ mice by performing RNA-sequencing. Several enriched signaling pathways were identified by Ingenuity Pathway Analysis (IPA), which seems to be mainly associated with cell skeleton signaling as well as signaling interaction between extracellular matrix and the cancer cell. A list of genes were validated by RT-PCR, and functional validation of these genes during the tumorigenesis in our animal model is to be carried out in the near future.
All Author(s) ListYan MF, Many A, Guan H, Or, MY, Chan ML
Name of ConferenceAmerican Association for Cancer Research Annual Meeting 2017
Start Date of Conference01/04/2017
End Date of Conference05/04/2017
Place of ConferenceWashington, DC
Country/Region of ConferenceUnited States of America
LanguagesEnglish-United States

Last updated on 2018-22-01 at 09:17